Inhibition of Aberrant Activated Fibroblast‐Like Synoviocytes in Rheumatoid Arthritis by Leishmania Peptide via the Regulation of Fatty Acid Synthesis Metabolism
Abstract The Leishmania homolog of receptors for activated C kinase (LACK) protein is derived from Leishmania parasites L. major. The polypeptide LACK156–173 has been shown to confer protection against murine autoimmune arthritis. Fibroblast‐like synoviocytes (FLSs) play a pivotal role in the synovi...
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Wiley
2025-05-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202409154 |
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| author | Jianling Su Xuemei Fan Yaoyao Zou Guangtao Fu Shiqi Feng Xiaoxue Wang Yongmei Yu Lin Li Zhenhua Bian Rongrong Huang Linmang Qin Jiping Chen Qin Zeng Kai Yan Caiyue Gao Zhexiong Lian Xin Li Yang Li |
| author_facet | Jianling Su Xuemei Fan Yaoyao Zou Guangtao Fu Shiqi Feng Xiaoxue Wang Yongmei Yu Lin Li Zhenhua Bian Rongrong Huang Linmang Qin Jiping Chen Qin Zeng Kai Yan Caiyue Gao Zhexiong Lian Xin Li Yang Li |
| author_sort | Jianling Su |
| collection | DOAJ |
| description | Abstract The Leishmania homolog of receptors for activated C kinase (LACK) protein is derived from Leishmania parasites L. major. The polypeptide LACK156–173 has been shown to confer protection against murine autoimmune arthritis. Fibroblast‐like synoviocytes (FLSs) play a pivotal role in the synovial invasion and joint destruction observed in rheumatoid arthritis (RA). The study reveals that LACK156‐173 can inhibit the aggressive phenotype of RA‐FLSs by restoring dysregulated fatty acid synthesis metabolism. In RA‐FLSs, overexpression of fatty acid synthase (FASN) leads to excessive fatty acid accumulation, which in turn promotes mitochondrial fragmentation by enhancing phosphorylation at the ser616 site of dynamin 1‐like protein (DRP1). This process increases reactive oxygen species (ROS) production and activates the PI3K/mTOR/NF‐κB pathway, thereby facilitating the transition of RA‐FLSs to an aggressive inflammatory and bone‐damaging phenotype. LACK156‐173 is internalized into the cytoplasm via CAPN2‐mediated endocytosis, where it directly binds to FASN and inhibits its activity. The findings suggest that targeting the restoration of fatty acid metabolism could potentially alleviate synovial invasion and joint damage in RA. LACK156‐173 may therefore hold therapeutic promise for RA patients. |
| format | Article |
| id | doaj-art-4e6a3ee786e04199b72ee01ee2d517af |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-4e6a3ee786e04199b72ee01ee2d517af2025-08-20T01:52:42ZengWileyAdvanced Science2198-38442025-05-011219n/an/a10.1002/advs.202409154Inhibition of Aberrant Activated Fibroblast‐Like Synoviocytes in Rheumatoid Arthritis by Leishmania Peptide via the Regulation of Fatty Acid Synthesis MetabolismJianling Su0Xuemei Fan1Yaoyao Zou2Guangtao Fu3Shiqi Feng4Xiaoxue Wang5Yongmei Yu6Lin Li7Zhenhua Bian8Rongrong Huang9Linmang Qin10Jiping Chen11Qin Zeng12Kai Yan13Caiyue Gao14Zhexiong Lian15Xin Li16Yang Li17Guangdong Cardiovascular Institute Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences Guangzhou 510000 ChinaDepartment of Rheumatology Zibo Central Hospital Zibo Shandong 255036 ChinaDepartment of Rheumatology and Immunology Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510000 ChinaDepartment of Orthopedics Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510000 ChinaGuangdong Cardiovascular Institute Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences Guangzhou 510000 ChinaThe First Affiliated Hospital of Shenzhen University Shenzhen Second People's Hospital Shenzhen University Shenzhen 518035 ChinaDepartment of Rheumatology and Immunology 2nd Affiliated Hospital of Harbin Medical University Harbin 150001 ChinaGuangdong Cardiovascular Institute Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences Guangzhou 510000 ChinaSchool of Biomedical Sciences and Engineering South China University of Technology Guangzhou International Campus Guangzhou 511442 ChinaDepartment of Pharmacy Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510080 ChinaDepartment of Rheumatology and Immunology Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510000 ChinaDepartment of Rheumatology and Immunology Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510000 ChinaGuangdong Cardiovascular Institute Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences Guangzhou 510000 ChinaMedical Research Institute Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510080 ChinaMedical Research Institute Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510080 ChinaGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510000 ChinaMedical Research Institute Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510080 ChinaDepartment of Rheumatology and Immunology Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510000 ChinaAbstract The Leishmania homolog of receptors for activated C kinase (LACK) protein is derived from Leishmania parasites L. major. The polypeptide LACK156–173 has been shown to confer protection against murine autoimmune arthritis. Fibroblast‐like synoviocytes (FLSs) play a pivotal role in the synovial invasion and joint destruction observed in rheumatoid arthritis (RA). The study reveals that LACK156‐173 can inhibit the aggressive phenotype of RA‐FLSs by restoring dysregulated fatty acid synthesis metabolism. In RA‐FLSs, overexpression of fatty acid synthase (FASN) leads to excessive fatty acid accumulation, which in turn promotes mitochondrial fragmentation by enhancing phosphorylation at the ser616 site of dynamin 1‐like protein (DRP1). This process increases reactive oxygen species (ROS) production and activates the PI3K/mTOR/NF‐κB pathway, thereby facilitating the transition of RA‐FLSs to an aggressive inflammatory and bone‐damaging phenotype. LACK156‐173 is internalized into the cytoplasm via CAPN2‐mediated endocytosis, where it directly binds to FASN and inhibits its activity. The findings suggest that targeting the restoration of fatty acid metabolism could potentially alleviate synovial invasion and joint damage in RA. LACK156‐173 may therefore hold therapeutic promise for RA patients.https://doi.org/10.1002/advs.202409154FASNfatty acid synthesis metabolismfibroblast‐like synoviocytesLeishmania receptors for activated C kinaserheumatoid arthritis |
| spellingShingle | Jianling Su Xuemei Fan Yaoyao Zou Guangtao Fu Shiqi Feng Xiaoxue Wang Yongmei Yu Lin Li Zhenhua Bian Rongrong Huang Linmang Qin Jiping Chen Qin Zeng Kai Yan Caiyue Gao Zhexiong Lian Xin Li Yang Li Inhibition of Aberrant Activated Fibroblast‐Like Synoviocytes in Rheumatoid Arthritis by Leishmania Peptide via the Regulation of Fatty Acid Synthesis Metabolism Advanced Science FASN fatty acid synthesis metabolism fibroblast‐like synoviocytes Leishmania receptors for activated C kinase rheumatoid arthritis |
| title | Inhibition of Aberrant Activated Fibroblast‐Like Synoviocytes in Rheumatoid Arthritis by Leishmania Peptide via the Regulation of Fatty Acid Synthesis Metabolism |
| title_full | Inhibition of Aberrant Activated Fibroblast‐Like Synoviocytes in Rheumatoid Arthritis by Leishmania Peptide via the Regulation of Fatty Acid Synthesis Metabolism |
| title_fullStr | Inhibition of Aberrant Activated Fibroblast‐Like Synoviocytes in Rheumatoid Arthritis by Leishmania Peptide via the Regulation of Fatty Acid Synthesis Metabolism |
| title_full_unstemmed | Inhibition of Aberrant Activated Fibroblast‐Like Synoviocytes in Rheumatoid Arthritis by Leishmania Peptide via the Regulation of Fatty Acid Synthesis Metabolism |
| title_short | Inhibition of Aberrant Activated Fibroblast‐Like Synoviocytes in Rheumatoid Arthritis by Leishmania Peptide via the Regulation of Fatty Acid Synthesis Metabolism |
| title_sort | inhibition of aberrant activated fibroblast like synoviocytes in rheumatoid arthritis by leishmania peptide via the regulation of fatty acid synthesis metabolism |
| topic | FASN fatty acid synthesis metabolism fibroblast‐like synoviocytes Leishmania receptors for activated C kinase rheumatoid arthritis |
| url | https://doi.org/10.1002/advs.202409154 |
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